Ignite Creation Date:
2024-05-05 @ 10:40 PM
Last Modification Date:
2024-10-26 @ 10:22 AM
Study NCT ID:
NCT01168167
Status:
COMPLETED
Last Update Posted:
2016-03-23
First Post:
2010-07-21
Brief Title:
Impact of Raltegravir on HIV-1 cDNA Slope Following Antiretroviral Therapy ART Initiation
Sponsor:
Christoph Stephan
Organization:
Goethe University
Study Overview
Official Title:
Comparing the Dynamics of Different HIV-1 cDNA Species in CD4-positive T-cells and HIV-1 RNA in Plasma of Infected Individuals After Initiation of Antiretroviral Therapy With or Without Raltegravir
Status:
COMPLETED
Status Verified Date:
2016-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Recent clinical trials of combination antiretroviral therapy cART containing the first approved integrase inhibitor ie raltegravir have demonstrated a more rapid decay of HIV-1 RNA in plasma compared to conventional potent antiretroviral combinations This was observed especially during the early phase up to week 12 following initiation of cART
To explain this two mechanistic hypotheses have been developed
1 - Macrophage reservoir death hypothesis A major source of virus production during the second phase decay are believed to be long-lived infected cells with continuous virus production - eg macrophages An accumulation of unintegrated episomal HIV-1 cDNAs can promote apoptosis Li et al Embo J 200120 3272 In case of HIV superinfection of such a productively infected cell an INI-based cART may induce apoptosis and thus contribute to a decrease in HIV RNA load during second phase decay However no study has thus far addressed the consequences of INI treatment on HIV-1 cDNA species on any cell population in vivo
2 - Resting CD4 T-cell reservoir integration block hypothesis Resting CD4 T-cells may represent a substantial reservoir for HIV replication during the second phase decay as well A special characteristic of these cells is that HIV-1 cDNA is typically localized to the nucleus in a not-integrated form Chun et al PNAS 19979413193 These resting cells likely integrate HIV-DNA upon activation and then contribute to HIV viremia and viral spread Conceptually integration could be prevented by RGV but not by RTI or PI An accumulation of circular episomal HIV-1 cDNA species may also be a consequence of RGV treatment in this cell type
Patient disposition
To explore raltegravir-induced shifts in HIV-1 cDNA species in vivo this non-interventional clinical observation investigates the dynamics of the three major HIV-1 cDNA species total HIV-1 cDNA HIV-1 integrants in the host cell genome episomal HIV-1 2-LTR circles over a period of 4 months in two groups of patients starting off cART from a single study center Patients who begin cART in regular clinical routine with 2NtRTI plus either n10 patients raltegravir or n10 patients a boosted protease inhibitor alternatively an NNRTI will be offered to participate in this observation Only patients are offered to participate in this trial if no other antiretroviral drugs than the above mentioned and no concomitant drugs with relevant impact on antiretrovirals pharmacokinetics are administered At time of study inclusion patients should be characterised by a HIV-1 RNA load of 5000 copiesmL and CD4-cell count of 200µL within 12 weeks before cART initiation
Preliminary analyses of PBMCs from HIV-infected patients indicate that all three major HIV-1 cDNA species can be quantified by real-time PCR under these baseline conditions
To explain this two mechanistic hypotheses have been developed
1 - Macrophage reservoir death hypothesis A major source of virus production during the second phase decay are believed to be long-lived infected cells with continuous virus production - eg macrophages An accumulation of unintegrated episomal HIV-1 cDNAs can promote apoptosis Li et al Embo J 200120 3272 In case of HIV superinfection of such a productively infected cell an INI-based cART may induce apoptosis and thus contribute to a decrease in HIV RNA load during second phase decay However no study has thus far addressed the consequences of INI treatment on HIV-1 cDNA species on any cell population in vivo
2 - Resting CD4 T-cell reservoir integration block hypothesis Resting CD4 T-cells may represent a substantial reservoir for HIV replication during the second phase decay as well A special characteristic of these cells is that HIV-1 cDNA is typically localized to the nucleus in a not-integrated form Chun et al PNAS 19979413193 These resting cells likely integrate HIV-DNA upon activation and then contribute to HIV viremia and viral spread Conceptually integration could be prevented by RGV but not by RTI or PI An accumulation of circular episomal HIV-1 cDNA species may also be a consequence of RGV treatment in this cell type
Patient disposition
To explore raltegravir-induced shifts in HIV-1 cDNA species in vivo this non-interventional clinical observation investigates the dynamics of the three major HIV-1 cDNA species total HIV-1 cDNA HIV-1 integrants in the host cell genome episomal HIV-1 2-LTR circles over a period of 4 months in two groups of patients starting off cART from a single study center Patients who begin cART in regular clinical routine with 2NtRTI plus either n10 patients raltegravir or n10 patients a boosted protease inhibitor alternatively an NNRTI will be offered to participate in this observation Only patients are offered to participate in this trial if no other antiretroviral drugs than the above mentioned and no concomitant drugs with relevant impact on antiretrovirals pharmacokinetics are administered At time of study inclusion patients should be characterised by a HIV-1 RNA load of 5000 copiesmL and CD4-cell count of 200µL within 12 weeks before cART initiation
Preliminary analyses of PBMCs from HIV-infected patients indicate that all three major HIV-1 cDNA species can be quantified by real-time PCR under these baseline conditions
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None